Phenotyping Mechanistic Pathways for Adverse Health Outcomes in Sleep Apnea

项目摘要/摘要 阻塞性睡眠呼吸暂停(OSA)是一种高度流行的疾病，具有不利的神经认知和心脏代谢 结果。持续正压通气(CPAP)是治疗呼吸道疾病的金标准治疗方案 睡眠障碍，从而预防其不利的心血管和神经认知结果。上一首 然而，临床试验在很大程度上未能显示CPAP对这些健康结果的持续影响。 我们认为，这些试验的主要局限性之一是对阻塞性睡眠呼吸暂停综合征及其急性发作的特征描述不足。 生理后果。通过根据“呼吸暂停低通气指数(AHI)”来描述阻塞性睡眠呼吸暂停综合征，有一个 潜在的负面结果风险。我们推测，通过更好地描述与OSA相关的生理 睡眠期间的不良后果，我们将能够识别出这些不良后果的高危个体，并 那些将从治疗中受益最多的人。我们已经开发了生理驱动的指标来捕获 阻塞性睡眠呼吸暂停低氧血症的准确负担(“低氧负担”)、自主神经反应(“心率负担”)，以及 睡眠碎片化(“唤醒负担”)。我们来自大型观测研究的初步数据表明，这些 这些指标的表现优于传统的睡眠研究参数。 在目标1中，我们试图证明高低氧负荷的OSA患者将表现出更大的改善， CPAP治疗12周后，在内皮功能(血流介导的血管扩张)和氧化应激方面 与低氧负荷的人相比，这一指标更高。在目标2中，我们将研究心率负担如何决定 CPAP治疗12周后24小时平均血压下降情况。最后，在目标3中，我们将寻求 为了证明睡眠碎片化程度较高的阻塞性睡眠呼吸暂停综合症患者，将通过唤醒负担来量化 在白天嗜睡和注意力的改善方面，CPAP的反应比CPAP更有利 低唤醒负担。虽然主要分析将是CPAP 12周后这些结果的变化， 我们还将在4周内评估这些结果，以检查它们的时间进程。共有158名男性和女性 有了呼吸暂停低通气指数≥，每小时15个事件将接受持续12周的持续呼吸支持。坚持治疗将是 通过定期电话和面对面访问对其进行仔细监测和鼓励。不良事件也将是 严密监控和记录。 总体而言，我们的建议有望证明阻塞性睡眠呼吸暂停综合征的预后标志物与 健康结果不仅将提高阻塞性睡眠呼吸暂停综合征的诊断水平，还将为识别 对CPAP治疗最敏感的个体。这些结果将对以下方面产生关键的机制影响 阻塞性睡眠呼吸暂停患者的“个体化用药”--将重点放在最能从CPAP中获益的患者群体上 心理治疗。这种个性化的医学方法将提供进步所需的科学知识 在选定的患者中进行更大规模的研究。这些结果具有重大意义，因为它们具有巨大的潜力 改善阻塞性睡眠呼吸暂停综合征患者的生活质量和健康结局。

PROJECT SUMMARY/ABSTRACT Obstructive sleep apnea (OSA) is a highly prevalent disorder with adverse neurocognitive and cardio-metabolic outcomes. Continuous positive airway pressure (CPAP) is the gold standard therapeutic option to treat airway obstructions during sleep and thus, prevent its adverse cardiovascular and neurocognitive outcomes. Previous clinical trials, however, have largely failed to show a consistent impact of CPAP on these health outcomes. One of the main limitations of these trials is, we believe, inadequate characterization of OSA and its acute physiological consequences. By characterizing OSA based on the “apnea-hypopnea index (AHI)”, there is a potential risk of negative results. We surmise that, by better characterization of OSA-related physiological consequences during sleep, we will be able to identify individuals at high risk for these adverse outcomes and those who would benefit most from therapy. We have developed physiologically driven metrics to capture the precise burden of OSA-related hypoxemia (“hypoxic burden”), autonomic response (“heart rate burden”), and sleep fragmentation (“arousal burden”). Our preliminary data from large observational studies suggest that these metrics outperform conventional sleep study parameters. In Aim 1, we seek to demonstrate that OSA patients with high hypoxic burden will exhibit greater improvements, after 12 weeks of CPAP therapy, in endothelial function (flow-mediated vasodilation) and oxidative stress markers than those with a low hypoxic burden. In Aim 2, we will investigate how heart rate burden determines the reduction in 24-hour mean blood pressure after 12 weeks of CPAP treatment. Finally, in Aim 3, we will seek to demonstrate that OSA patients with larger degrees of sleep fragmentation, quantified by arousal burden, will respond more favorably to CPAP, in terms of improvement in daytime sleepiness and attention, than those with low arousal burden. While the primary analysis will be the change in these outcomes after 12 weeks of CPAP, we will also assess these outcomes at 4 weeks to examine their time course. A total of 158 men and women with apnea-hypopnea index ≥15 events/hour will receive CPAP for 12 weeks. Adherence to therapy will be carefully monitored and encouraged by regular phone calls and in-person visits. Adverse events will also be closely monitored and recorded. Overall, our proposal is expected to demonstrate that prognostic markers of OSA that more strongly link with health outcomes will not only improve the diagnosis of OSA, but also provide a physiological basis for identifying those individuals most responsive to CPAP therapy. These results will have key mechanistic implications for “individualized medicine” in OSA by focusing on subgroups of patients who would most benefit from CPAP therapy. This personalized medicine approach will provide the scientific knowledge needed to progress towards larger studies in selected patients. Such results are of major importance because they have great potential to improve the quality of life and health outcomes of patients with OSA.